Non-small cell lung cancer (NSCLC) affects over 222,000 Americans annually. Despite advances in therapy, the 5-year survival rate is as low as 15%. Current treatments of NSCLC include cytotoxic chemotherapy and targeted biologic therapies. They all have multiple shortcomings including only a modest increase in survival and significant toxicity to the patient. The limitations in efficacy and safety associated with availabe treatments for NSCLC highlight the need for new treatments. As found recently, triggering receptor expressed on myeloid cells (TREM-1) plays a role in NSCLC progression. Inhibition of TREM-1 by short hairpin RNA (shRNA) in macrophages is shown to suppress cancer cell invasion. In clinical setting, the 4-year survival rate in patients with low expression of TREM-1 on tumor-associated macrophages (TAMs) is 60%, compared with 20% in those with high expression. We hypothesize that TREM-1 inhibition can improve survival of NSCLC patients. The long-term objective of the proposed project is to develop a novel approach to targeted treatment of NSCLC. The major goal of the Phase I study is to demonstrate that specific inactivation of TREM-1 with novel inhibitory peptides suppresses tumor progression in animal model system and improves survival. Phase I specific aims are to: 1) generate and characterize injectable formulations of TREM-1 inhibitory peptides, and 2) test the TREM-1 inhibitory peptides in a mouse model of NSCLC. The peptides will be designed using SignaBlok's proprietary model of TREM-1 signaling. These peptides employ novel, ligand-independent mechanisms of action and are anticipated to have less severe side effects. In order to increase peptide solubility, bioavailability and targeting to TAMs, we will utilize SignaBlok's proprietary nanosystem for macrophage-targeted delivery of water insoluble and poorly water soluble drugs. We will use a NCI-H292 xenograft mouse model of NSCLC to test the ability of the peptides in free and particulate forms to inhibit cancer progression and promote survival. It is anticipated that the proposed research will identify novel anticancer lead compounds that will set the stage for the development of new targeted therapies of NSCLC, thereby leading to a higher survival rate of the patients. The Phase I data will be used to further improve this technology in a Phase II program. Importantly, TREM-1 may play a role in the progression of not only NSCLC but also other tumors. Thus, successful completion of Phase I will provide the proof of concept of the hypothesis that might be applicable to a variety of tumors. PUBLIC HEALTH RELEVANCE: Non-small cell lung cancer kills more patients than breast, colon, and prostate cancer combined, and the 5- year survival rate is 15%. Current treatment has multiple shortcomings including only a modest increase in survival and significant toxicity to the patient. The proposed research is expected to result in the development of novel anticancer therapeutics that could substantially improve treatment of this type of cancer, thereby leading to a higher survival rate of the patients.